There are over 6000 disorders in humans that result from a single gene mutation (Rappaport et al. 2013). For many of these conditions, there is no suitable animal model. Because rhesus macaques are genetically and physiologically similar to humans, they have the potential to offer preclinical models for numerous human conditions. We have preliminary data demonstrating that we can identify loss-of-function mutations in rhesus macaques related to human disease from exome sequencing, validate these results with PCR and Sanger sequencing and establish loss-of-function at the protein level. The overall goal of this proposal is to produce rhesus macaque models of single gene human genetic disorders. To accomplish this, we will identify naturally occurring loss-of-function mutations in rhesus macaques at the Yerkes National Primate Research Center (YNPRC). We already have exome sequence data from 61 animals. We will identify loss- of-function mutations in genes using the GATK pipeline and then validate these mutations with PCR/Sanger sequencing. Because these mutations are likely to be present in the heterozygous state, we propose to genotype 500 breeding rhesus macaques for a subset of the newly identified loci. The loci we choose to genotype will be based on whether the polymorphism leads to a predicted loss of function within genes implicated in human disease. After genotyping and identification of a sufficient number of animals that have the same mutation, we will breed multiple male and female heterozygotes with the expectation that 25% of the resulting offspring will be homozygous for the mutation. We expect that these animals will exhibit a phenotype similar to humans with loss-of-function mutations in the orthologous gene and serve as models for preclinical translational studies to begin to identify possible treatment strategies. When completed, this proposal will produce three distinct deliverables. 1) A catalog of high impact polymorphism present within a subset of the Yerkes rhesus population. 2) Proof of concept in an affected offspring that will serve as a model in the study of human single gene disorders. 3) Development of a pipeline to produce additional rhesus models of human genetic disease at Yerkes and other institutions.